INHIBITION OF MULTIPLICATION 197 



made in the absence of the substance. It is surprising how infrequently this 

 direct approach has been employed. 



There are, it appears, a number of discrete steps in the complex process of 

 virus reproduction. Present evidence indicates that some inhibitory substances 

 act to alter one step but may not affect others. In most instances, however, 

 there is little information that bears directly on the mechanism of inhibition 

 and it is difficult to discover whether virus attachment, penetration, intracel- 

 lular biosynthesis, assembly and maturation, or release were affected. It will 

 be apparent that these terms, which identify certain of the well-recognized 

 steps in the multiplication process, come from the current scheme concerning 

 bacterial viruses. A diminished yield of virus may indicate that inhibition has 

 been produced, but it leaves unanswered the more important question: What 

 process was inhibited? Much more rewarding information is secured when 

 studies are designed to provide information about the step or steps in the 

 multiplication process that are affected. 



When study of the inhibition of virus multiplication is correlated as closely 

 as possible with studies of the multiplication process per se, new information 

 on either problem may contribute to advances regarding the other. From the 

 broad viewpoint these two aspects of the problem are so closely related as to 

 be almost inseparable and probably are most effectively approached simul- 

 taneously. 



Throughout, this chapter, a sharp distinction is made between prevention 

 of infection, on the one hand, and inhibition of intracellular multiplication, 

 on the other. This is considered to be important because both may lead to an 

 identical operational result, i.e., a diminished yield of new virus particles, 

 even though the mechanisms involved may be wholly dissimilar. Substances 

 which are highly effective in preventing infection, e.g., specific antibody, may 

 have little or no effect upon intracellular multiplication. Similarly, substances 

 which are very potent inhibitors of intracellular multiplication, e.g., certain 

 chloro-glycosyl derivatives of benzimidazole (Tamm, 1956a) may be entirely 

 incapable of preventing infection of a susceptible host cell. 



By design, an effort is made also to distinguish clearly between the funda- 

 mental biological unit, i.e., the single virus-infected cell, and the experimental 

 material which is, in the great majority of instances, either a tissue culture 

 system, a separated tissue, or an intact animal infected by a virus. As will be 

 evident, this distinction is possible less commonly than is desirable in 

 experiments with inhibitory materials. When inferences can be drawn at the 

 level of the virus-infected cell, many of the uncertainties which stem from 

 assumptions made in studies with the intact animal host are removed. 

 Seemingly crucial variables, such as the size of the inoculum, the time between 

 inoculation and administration of the inhibitory substance, the presence or 

 absence of gross lesions, and others, have little relevance to events occurring 



